Journal ArticleDOI
Blood–Brain Barrier Transport of Kynurenines: Implications for Brain Synthesis and Metabolism
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TLDR
The results demonstrate the saturable transfer of L‐KYN across the blood–brain barrier and suggest that circulating L‐ KYN, 3‐HKYN, and ANA may each contribute significantly to respective cerebral pools under normal conditions.Abstract:
To evaluate the potential contribution of circulating kynurenines to brain kynurenine pools, the rates of cerebral uptake and mechanisms of blood-brain barrier transport were determined for several kynurenine metabolites of tryptophan, including L-kynurenine (L-KYN), 3-hydroxykynurenine (3-HKYN), 3-hydroxyanthranilic acid (3-HANA), anthranilic acid (ANA), kynurenic acid (KYNA), and quinolinic acid (QUIN), in pentobarbital-anesthetized rats using an in situ brain perfusion technique. L-KYN was found to be taken up into brain at a significant rate [permeability-surface area product (PA) = 2-3 x 10(-3) ml/s/g] by the large neutral amino acid carrier (L-system) of the blood-brain barrier. Best-fit estimates of the Vmax and Km of saturable L-KYN transfer equalled 4.5 x 10(-4) mumol/s/g and 0.16 mumol/ml, respectively. The same carrier may also mediate the brain uptake of 3-HKYN as D,L-3-HKYN competitively inhibited the brain transfer of the large neutral amino acid L-leucine. For the other metabolites, uptake appeared mediated by passive diffusion. This occurred at a significant rate for ANA (PA, 0.7-1.6 x 10(-3) ml/s/g), and at far lower rates (PA, 2-7 x 10(-5) ml/s/g) for 3-HANA, KYNA, and QUIN. Transfer for KYNA, 3-HANA, and ANA also appeared to be limited by plasma protein binding. The results demonstrate the saturable transfer of L-KYN across the blood-brain barrier and suggest that circulating L-KYN, 3-HKYN, and ANA may each contribute significantly to respective cerebral pools. In contrast, QUIN, KYNA, and 3-HANA cross the blood-brain barrier poorly, and therefore are not expected to contribute significantly to brain pools under normal conditions.read more
Citations
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Journal ArticleDOI
Perinatal kynurenine 3-hydroxylase inhibition in rodents: Pathophysiological implications
TL;DR: It is demonstrated that acute kynurenine 3‐hydroxylase inhibition effectively shifts cerebral KP metabolism in neonatal rodents toward increased KYNA formation, and selective inhibitors of this enzyme may provide neuroprotection in newborns and will also be useful for the experimental evaluation of the long‐term effects of perinatal KP impairment.
Journal ArticleDOI
Prenatal Dynamics of Kynurenine Pathway Metabolism in Mice: Focus on Kynurenic Acid.
Nick Goeden,Francesca M. Notarangelo,Ana Pocivavsek,Sarah Beggiato,Alexandre Bonnin,Robert Schwarcz +5 more
TL;DR: Investigating the prenatal features of KP metabolism in vivo with special focus on KYNA found that only a very small fraction of maternal kynurenine is converted to KYNA in the placenta and released into the fetal compartment under physiological conditions, helping to clarify the contributions of the maternal circulation and the Placenta to fetal KYNA during the late prenatal period.
Journal ArticleDOI
High tryptophan diet reduces extracellular dopamine release via kynurenic acid production in rat striatum.
TL;DR: In this article, male Wistar rats were fed a high tryptophan diet for 24 hours to examine the effect of increased TPN on extracellular dopamine (DA) and kynurenic acid (KYNA).
Book ChapterDOI
Modulation of the Kynurine Pathway of Tryptophan Metabolism in Search for Neuroprotective Agents. Focus on Kynurenine-3-Hydroxylase
Roberto Pellicciari,Laura Amori,Gabriele Costantino,Antonio Giordani,Antonio Macchiarulo,L. Mattoli,Paolo Pevarello,C. Speciale,Mario Varasi +8 more
TL;DR: Data support the notion that kynurenine-3-hydroxylase inhibitors may have a sustained therapeutic potential in those diseases characterized by unbalance in the QUIN/KYNA branches of the kynuranine pathway.
Journal ArticleDOI
Low Serum Tryptophan Levels as an Indicator of Global Cognitive Performance in Nondemented Women over 50 Years of Age
L. A. Ramos-Chávez,Gabriel Roldán-Roldán,B. García-Juárez,Dinora F. González-Esquivel,G. Pérez de la Cruz,Benjamín Pineda,Daniela Ramírez-Ortega,I. García Muñoz,B. Jiménez Herrera,Camilo Ríos,Saúl Gómez-Manzo,Jaime Marcial-Quino,L. Sánchez Chapul,P. Carrillo Mora,V. Pérez de la Cruz +14 more
TL;DR: Evaluating the relation between the changes in Trp catabolism and cognitive impairment associated with age through KP metabolites level alterations in women over 50 years of age concluded that KP activation increases with age and it is strongly associated with the level of cognition performance in nondemented women over50 years ofAge.
References
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Journal ArticleDOI
Quinolinic acid: an endogenous metabolite that produces axon-sparing lesions in rat brain
TL;DR: Intracerebral injection of the neuroexcitatory tryptophan metabolite, quinolinic acid, has behavioral, neurochemical and neuropathological consequences reminiscent of those of exogenous excitotoxins, such as kainic and ibotenic acids.
Journal ArticleDOI
Distinct mediating systems for the transport of neutral amino acids by the ehrlich cell
Journal ArticleDOI
Amino acid assignment to one of three blood-brain barrier amino acid carriers
William H. Oldendorf,John Szabo +1 more
TL;DR: Affinity for a basic amino acid carrier system was demonstrated for arginine, ornithine, and lysine and a third, low-capacity independent carrier system transporting aspartic and glutamic acids was demonstrated.
Journal ArticleDOI
An in situ brain perfusion technique to study cerebrovascular transport in the rat
TL;DR: The in situ brain perfusion technique is a sensitive new method to study cerebrovascular transfer in the rat and permits absolute control of perfusate composition.